Genetic and epidemiological aspect of Complex Regional Pain Syndrome
Rooij, A.M. de
Citation
Rooij, A. M. de. (2010, April 27). Genetic and epidemiological aspect of Complex Regional Pain Syndrome. Retrieved from https://hdl.handle.net/1887/15335
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2 Spontaneous onset of Complex Regional Pain Syndrome
Annetje M. de Rooij a Roberto S.G.M. Perez b,c Frank J. Huygen d Frank van Eijs e Maarten van Kleef f Martin C.R. Bauer g Jacobus J. van Hilten a Johan Marinus a
a Department of Neurology, Leiden University Medical Center, Leiden, The Netherlands.
b Department of Anesthesiology, VU University Medical Center, Amsterdam, The Netherlands.
c Research Institute for Extramural Medicine (EMGO), Amsterdam, The Netherlands.
d Department of Anesthesiology, Erasmus Medical Center, Rotterdam, The Netherlands.
e Department of Anesthesiology, Sint Elisabeth Hospital, Tilburg, The Netherlands.
f Department of Anesthesiology, Academic Hospital Maastricht, Maastricht, The Netherlands.
g Department of Anesthesiology, Leiden University Medical Center, Leiden, The Netherlands.
European Journal of Pain. 2009 Sep 28. (Epub ahead of print)
Chapter 2
Abstract
Complex Regional Pain Syndrome (CRPS) usually develops after a noxious event, but spontaneous onsets have been described in 3-11% of the cases. The existence of spontaneous-onset CRPS is highly debated and the aim of the present study was therefore to compare the phenotypic characteristics of CRPS patients with a spontaneous onset, with those of patients with a trauma-induced onset.
Data of 537 CRPS patients followed up at four departments of anesthesiology were analyzed and comprised 498 (93%) patients with and 39 (7%) patients without a known eliciting event. There where no significant differences between the two groups in gender, or in onset in upper or lower limb or left or right side of the body.
Compared to CRPS patients with a trauma-induced onset, spontaneous-onset cases were on average 9 years younger at disease onset and had a 1.4 years longer median disease duration. No significant differences in frequency were found for any of the 34 compared signs and symptoms when the effect of multiple testing was controlled.
In conclusion, CRPS may develop both with and without a precipitating noxious event, with both groups exhibiting a largely similar clinical presentation. Spontaneous- onset CRPS patients generally develop the syndrome at a younger age, possibly indicating a susceptibility to develop the condition. The longer disease duration in spontaneous-onset cases may reflect a more gradual disease onset, poorer prognosis, or a delay in diagnosis, possibly as a result of reluctance to make this diagnosis in the absence of a clear initiating event.
Spontaneous onset of Complex Regional Pain Syndrome
29
Introduction
Complex Regional Pain Syndrome (CRPS) is characterized by pain and different combinations of sensory, vasomotor, sudomotor, motor and trophic disturbances.1 The syndrome develops after a noxious event, such as fracture, sprain or operation, in the vast majority (89-97%) of cases.2,3,4,5,6,7 This noxious stimulus apparently sets off a complex interplay of different pathogenic mechanisms that may contribute to the development of this syndrome.8,9 In the other 3-11% of the cases, however, CRPS develops without a clear causative event;10,11,12,13,14,15 no apparent trigger could be identified and the syndrome is considered to have developed spontaneously. The question whether CRPS may indeed develop spontaneously has often been a subject of debate among clinicians and researchers.
Interestingly, the diagnostic criteria for CPRS formally accepted by the International Association for the Study of Pain (IASP) do not rule out the possibility of spontaneous onset of CRPS. Although the first criterion describes that CRPS develops after an initiating noxious event, the footnote in the official publication states that this criterion does not have to be fulfilled in order to make the diagnosis.1 Nevertheless, some authors omit this footnote when reporting the IASP criteria16,17 and the incomplete description of the diagnostic criteria may have led to unnecessary restriction to only those patients in whom the condition developed after a causative event.18,19,20 The different descriptions may result in confusion regarding the acceptability of a spontaneous onset of the syndrome. Other commonly applied diagnostic criteria, like those developed by Harden and Bruehl,21,22 and Veldman et al.,23 also allow for the possibility of spontaneous onset.
Researchers may however have other reasons to exclude non-traumatic onset cases from studies. A potential advantage of excluding these patients could be the supposed improved homogeneity of the study population, though, possibly, at the expense of introducing increased heterogeneity between studies. The question then arises whether differences between trauma-onset cases (tCRPS) and spontaneous-onset cases (sCRPS) indeed justify the exclusion of the latter group from studies.
The objective of the present study is to compare patient characteristics and clinical features of CRPS patients with a spontaneous onset with those of patients with a trauma-induced onset, and to identify any relevant differences between the two groups.
Chapter 2
Methods
Patients
Between July 2004 and November 2008, 537 CRPS patients were included from four outpatient pain clinics at departments of anesthesiology that participate in the Trauma RElated Neuronal Dysfunction (TREND) Consortium
(http://www.trendconsortium.nl/). In TREND, the acquisition of data concerning the clinical diagnosis and other phenotypic characteristics is performed in a standardized manner, after which this information is stored in a central internet-based database. Information about signs (observed by examiner) and symptoms (reported by patients) were collected using a standard assessment form on which information on pain, sensory impairments, autonomic impairments, trophic changes and motor impairments was recorded. The features were registered as dichotomous variables (i.e., present or absent).
Patients were included if the IASP criteria for the diagnosis of CRPS were fulfilled 1. Two groups were constructed based on the presence (tCRPS; N=498 [93%]) or absence (sCRPS; N=39 [7%]) of a known noxious event before the development of the syndrome. The reported noxious events of tCRPS patients involved fractures (38%), operations (27%), soft tissue injuries (27%) and miscellaneous causes (8%).
The percentage of sCRPS patients in the four different departments of anesthesiology ranged between 5% and 9%. The date of trauma was used to determine disease onset in tCRPS patients; in sCRPS patients, disease onset was determined by the start of the first symptoms as indicated by the patient. Patients’ characteristics and frequency of signs and symptoms were compared between the two groups.
Statistical analysis
Differences in the occurrence of signs and symptoms between the sCRPS and tCRPS patient groups were calculated using Chi-square (χ2) tests. P values were considered significant if <0.05.To account for the fact that both groups were compared with respect to the presence of 34 signs and symptoms, a Bonferroni-correction was applied,24 resulting in an adjusted P value of 0.00147. Continuous variables were compared with a t-test for independent samples or Mann-Whitney U tests as appropriate.
The 95% confidence intervals (CI) for the between-group differences were calculated using Newcombe’s method.25 Statistical analyses were performed with the Statistical Package for the Social Sciences (version 16) and Confidence Interval Analysis (version 2.1.2).
Spontaneous onset of Complex Regional Pain Syndrome
31
The study was approved by the Medical Ethical Committee of the involved medical centers. All patients gave written informed consent before participation.
Results
Patients’ demographics for both groups are summarized in Table 1. There where no statistically significant differences between the sCRPS and tCRPS patients with respect to gender, side of onset and onset in upper or lower extremity. Compared to tCRPS patients, sCRPS patients were on an average 8.6 years younger at disease onset (38.2 versus 46.8; 95% Confidence Interval of the difference [95% CIdiff.]: 3.4 to 13.8). The difference in median disease duration between sCRPS and tCRPS patients was 1.4 years (1.8 versus 0.4; 95% CIdiff.: 0.3 to 2.5).
Table 2 shows the presence of signs and symptoms in the two groups. The proportion of missing data was low (<8%) in both groups. After correction for multiple testing no significant differences were found between the sCRPS and tCRPS patients. In 62%
of the variables the differences in frequency of signs and symptoms was 5% or less and in 91% of the variables the difference was 15% or less. In 65% of the symptoms and 76% of the signs, the percentage was equal or higher among sCRPS patients in comparison to tCRPS patients.
Chapter 2
Table 1: Characteristics of spontaneous and trauma CRPS patients
Spontaneous Trauma P-Value
Number of patients 39 498
Percentage of females (N) 74% (29) 82% (409) 0.23a
Mean (SD) age at onset of CRPS – years 38.2 (15.3) 46.8 (15.8) 0.001b Median (IQR) disease duration – years 1.8 (0.4 to 4.0) 0.4 (0.2 to 1.5) <0.0005c Percentage fulfilling Budapest criteria e (N) 33% (13) 31% (153) 0.79 a Mean (SD) VAS pain score 6.35 (1.7) d 6.26 (2.0) d 0.20 b
First affected extremity – Percentage (N) 0.67 a
Arm 44% (17) 51% (252)
Leg 56% (22) 49% (245)
Both 0% (0) 0% (1)
First affected side –Percentage (N) 0.45 a
Right 56% (22) 48% (237)
Left 44% (17) 51% (253)
Both 0% (0) 2% (8)
Pain medication
% Paracetamol/NSAID 38%d 38% d 0.99 a
% Mild opioids and co-analgetics1 38% d 32% d 0.47 a
% Strong opioids 3% d 7% d 0.53 a
CRPS= Complex Regional Pain Syndrome. N= Number. SD= Standard deviation. IQR= Interquartile range. VAS= Visual Analogue Scale. NSAID=Non-Steroidal Anti-Inflammatory Drugs. 1 Co-analgetics include tricyclic antidepressants and anticonvulsive medication.
a: Chi-square test; b: T-test for independent samples; c: Mann-Whitney U test.
d: Percentages were calculated from non-missing data. e: 26
Table 2 Signs and symptoms in spontaneous CRPS patients and trauma CRPS patients
Symptoms (subjective) Signs (objective)
Spontaneous
(N=39) Trauma (N=498) P-valuea
Spontaneous
(N=39) Trauma (N=498) P-Valuea
N % N % N % N %
Allodynia 21 54% 241 49% 0.52 24 62% 321 65% 0.69
Hyperesthesia 13 33% 153 31% 0.78 14 36% 171 35% 0.89
Hypoesthesia 6 16% 91 19% 0.69 15 41% 138 29% 0.13
Hyperalgesia 16 41% 232 47% 0.46 20 51% 239 49% 0.75
Hypoalgesia 3 8% 33 7% 0.79 14 38% 83 18% 0.002
Asymmetry in color 29 74% 368 74% 1.00 27 69% 329 67% 0.72
Asymmetry in temperature 30 81% 368 76% 0.47 23 62% 299 62% 0.95
Edema 27 69% 359 73% 0.63 18 46% 302 61% 0.06
Asymmetry in sweating 23 59% 230 46% 0.13 10 26% 101 20% 0.43
Trophic disturbances 21 54% 292 59% 0.56 15 39% 261 52% 0.09
Muscle atrophy 6 16% 79 16% 0.97 10 27% 84 18% 0.15
Decreased range of motion 24 63% 319 66% 0.78 29 76% 369 76% 0.96
Weakness 22 56% 285 60% 0.64 25 64% 224 47% 0.04
Dystonia 17 44% 169 34% 0.24 3 8% 37 8% 0.97
Tremor 15 39% 126 26% 0.08 3 8% 28 6% 0.61
Myoclonus 14 38% 97 20% 0.01 1 3% 8 2% 0.64
Bradykinesia 11 31% 111 24% 0.36 18 50% 239 51% 0.90
Percentages were calculated using non-missing data. CRPS= Complex Regional Pain Syndrome. N= Number. a:
3 signs and symptoms were significant at the 0.05 level, though none reached Bonferroni-adjusted significance (P<0.00147).
Chapter 2
Discussion
In the present study, we demonstrated that Complex Regional Pain Syndrome (CRPS) may develop both with and without a precipitating noxious event, with both groups exhibiting a largely similar clinical presentation. We compared the phenotypic characteristics of patients with a spontaneous onset (sCRPS) with those of patients with a trauma-induced onset (tCRPS). No significant differences were found between sCRPS and tCRPS patients in gender, or in onset in upper or lower limb, or left or right side of the body. Compared to tCRPS patients, sCRPS patients were on average 9 years younger at disease onset. A similar observation, that is, younger age at onset in combination with a more frequent spontaneous onset, has previously been reported in other comparative studies. De Rooij et al.27 found that in comparison with sporadic (i.e., non-familial) CRPS patients, familial CRPS patients had a 8 year younger age at onset (33.9 years versus 41.9 years) while familial patients also more often developed the syndrome spontaneously (26% versus 16%). Veldman and Goris28 reported that CRPS patients in whom the disease recurred in the same or another extremity, showed a younger median age at onset (35 years versus 41 years) in combination with a more frequent spontaneous onset (16% versus 10%). Together these observations may hint at an increased susceptibility to develop this condition, possibly on the basis of genetic vulnerability.
There may be three explanations for the longer disease duration of sCRPS patients in comparison with tCRPS patients. Firstly, this may reflect reluctance among physicians to consider the diagnosis of CRPS in the absence of a clear initiating event, which may lead to a delay in referral to CRPS specialist centers for further diagnostics. It is important to prevent this delay in view of the fact that early and adequate treatment of CRPS may improve disease course and outcome.29,30 Secondly, the longer disease duration may reflect the previously reported poorer prognosis of patients who develop the syndrome after a less severe trauma (or, in this case, no trauma at all).
Sandroni et al. and De Mos et al. found that injuries other than fracture (which generally are less severe) had a poorer outcome.31,32 It would seem plausible that patients who develop CRPS after a less severe trauma or no trauma at all have an increased vulnerability to develop the syndrome, which likely will have consequences for prognosis and duration of recovery. Finally, the longer disease duration could be a consequence of a slower disease progression in sCRPS patients, which could lead to a delay in referral to CRPS specialist centers.
Spontaneous onset of Complex Regional Pain Syndrome
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None of the 34 signs and symptoms that were compared between the sCRPS and tCRPS patients differed significantly after correction for multiple testing. If there were doubt regarding the validity of the diagnosis of sCRPS, one might expect that there would be marked discrepancies between the reported symptoms and the observed signs, with signs occurring more frequently among tCRPS patients and symptoms occurring more frequently among sCRPS patients, but this was not the case. In 76%
of the signs, they were either distributed equally or more often present in sCRPS.
Additionally, there is a large similarity between both groups; in 62% of the variables the differences in frequency of signs and symptoms was 5% or less.
Using three different diagnostic criteria sets for CRPS, Perez et al. found that the features that best discriminated between patients who fulfilled all or none of these sets were reported hyperesthesia and allodynia, along with observed color asymmetry, hyperesthesia, temperature asymmetry and edema.33 However, we found that the percentage of all these signs and symptoms were not significantly different between sCRPS and tCRPS patients, which again underlines the similarity of the two groups.
One may question whether psychological stress could play a role in the onset of CRPS in cases with a spontaneous onset. The “fight or flight” reaction in stress causes a release of pro-inflammatory cytokines independent of endotoxemia, tissue injury, or inflammation.34,35 The same cytokines are suggested to play a major role in the acute phase of CRPS36,37 and one could therefore argue that psychological stress primes the body for an immune response, thereby reducing the threshold for the aberrant inflammation reaction seen in CRPS. Unfortunately, we have no information on the presence or severity of psychological stress in the period before onset of CRPS of our patient group. There is, however, increasing evidence that, at least at the group level, the role of psychological factors in the onset of the condition is negligible.38 In a large, recently published population-based case-control study in which patients who developed CRPS were compared with age and sex matched controls who did not develop CRPS after a similar trauma, no significant differences in psychological factors were found in the period before onset in the medical records of subjects of both groups.39 This does not rule out the possibility that the role of psychological stress would be different in cases with a spontaneous onset, but unfortunately the number of sCRPS patients in that study was too low (n=15; 8%) to draw any conclusions. Nevertheless, if psychological stressors would indeed play an important role in the onset of sCRPS, one would expect to find at least some influence in the onset tCRPS as well, which, as mentioned, was not the case which makes this explanation less probable.
Chapter 2
One of the strengths of the present study is the large number of patients collected, which lends support to the credibility of the findings. Although the information on signs and symptoms was collected by different examiners, which may have led to an increase in variability in the evaluation of signs and symptoms, there is little reason to assume that this variability affected both groups differentially and would have led to bias in any direction. Additionally, to reduce variability, uniform guidelines for data collection were provided and methods of examining patients were standardized across centers.
Another point that should be considered is the certainty that there was no noxious event before the onset of the syndrome in sCRPS patients. This depends first of all on the memory of the patient. It is known that even a very minor trauma can trigger the onset of CRPS,40 which raises the possibility that patients do not relate this minor trauma to the ensuing development of CRPS, especially after a long disease duration.
Another possibility is that symptoms may not have developed directly after the noxious event, but after a certain amount of time, which also would make it more difficult to recognize the association between trauma and CRPS. It is, on the other hand, also possible that the number of spontaneous CRPS patients is underestimated because the first signs of a spontaneous CRPS may have faultily been attributed to questionable causes, such as, for instance, overuse.
Taken together, the present study shows that CRPS may develop spontaneously with somatic features that are very similar to those of patients in whom the syndrome developed after a trauma. This underlines that a noxious event is a likely though not necessary component in the causal pie model of CRPS; in stead, the onset of the syndrome may be considered multifactorial in nature, with extrinsic (i.e., environmental) and intrinsic (i.e., genetic) factors interacting. It is important that only one set of IASP criteria is used in future studies. The current study shows that there is little reason to deviate from the originally agreed IASP criteria as presented by Merskey and Bogduk. We also found that CRPS patients with a spontaneous onset contract the condition at a younger age, possibly indicating a predisposition to develop the disease. The longer disease duration found in patients with a spontaneous onset may reflect a delay in diagnosis, possibly as a result of the reluctance to make the diagnosis in the absence of trauma, a situation that should be avoided given the better chances of success if treatment is initiated early.
Spontaneous onset of Complex Regional Pain Syndrome
37 Reference List
1. Merskey H and Bogduk N Complex Regional Pain Syndrome, Type I. In: Merskey, H. and Bogduk, N., editors. Classification of chronic pain: descriptions of chronic pain syndromes and definitions of pain terms. Seattle: IASP Press; 1994. pp. 41-42.
2. Allen G, Galer BS, and Schwartz L. Epidemiology of complex regional pain syndrome: a retrospective chart review of 134 patients. Pain 1999;80: 539-544 3. Geertzen JH, Dijkstra PU, Groothoff JW, ten Duis HJ, and Eisma WH. Reflex
sympathetic dystrophy of the upper extremity--a 5.5-year follow-up. Part I.
Impairments and perceived disability. Acta Orthop Scand Suppl 1998;279: 12-18 4. Kurvers HA, Jacobs MJ, Beuk RJ, Van den Wildenberg FA, Kitslaar PJ, Slaaf DW,
and Reneman RS. Reflex sympathetic dystrophy: evolution of microcirculatory disturbances in time. Pain 1995;60: 333-340
5. van der Laan L, Veldman PH, and Goris RJ. Severe complications of reflex sympathetic dystrophy: infection, ulcers, chronic edema, dystonia, and myoclonus.
Arch Phys Med Rehabil 1998;79: 424-429
6. Veldman PH, Reynen HM, Arntz IE, and Goris RJ. Signs and symptoms of reflex sympathetic dystrophy: prospective study of 829 patients. Lancet 1993;342: 1012- 1016
7. Veldman PH and Goris RJ. Multiple reflex sympathetic dystrophy. Which patients are at risk for developing a recurrence of reflex sympathetic dystrophy in the same or another limb. Pain 1996;64: 463-466
8. Birklein F. Complex regional pain syndrome. J Neurol 2005;252: 131-138
9. de Mos M, Sturkenboom MC, and Huygen FJ. Current Understandings on Complex Regional Pain Syndrome. Pain Pract 2009;9: 86-99
10. Allen G, Galer BS, and Schwartz L. Epidemiology of complex regional pain syndrome: a retrospective chart review of 134 patients. Pain 1999;80: 539-544 11. Geertzen JH, Dijkstra PU, Groothoff JW, ten Duis HJ, and Eisma WH. Reflex
sympathetic dystrophy of the upper extremity--a 5.5-year follow-up. Part I.
Impairments and perceived disability. Acta Orthop Scand Suppl 1998;279: 12-18 12. Kurvers HA, Jacobs MJ, Beuk RJ, Van den Wildenberg FA, Kitslaar PJ, Slaaf DW,
and Reneman RS. Reflex sympathetic dystrophy: evolution of microcirculatory disturbances in time. Pain 1995;60: 333-340
13. van der Laan L, Veldman PH, and Goris RJ. Severe complications of reflex sympathetic dystrophy: infection, ulcers, chronic edema, dystonia, and myoclonus.
Arch Phys Med Rehabil 1998;79: 424-429
14. Veldman PH, Reynen HM, Arntz IE, and Goris RJ. Signs and symptoms of reflex sympathetic dystrophy: prospective study of 829 patients. Lancet 1993;342: 1012- 1016
15. Veldman PH and Goris RJ. Multiple reflex sympathetic dystrophy. Which patients are at risk for developing a recurrence of reflex sympathetic dystrophy in the same or another limb. Pain 1996;64: 463-466
Chapter 2
16. Birklein F, Riedl B, Neundorfer B, and Handwerker HO. Sympathetic vasoconstrictor reflex pattern in patients with complex regional pain syndrome. Pain 1998;75: 93-100
17. Stanton-Hicks M, Janig W, Hassenbusch S, Haddox JD, Boas R, and Wilson P.
Reflex sympathetic dystrophy: changing concepts and taxonomy. Pain 1995;63: 127- 133
18. Oakley JC and Weiner RL. Spinal cord stimulation for complex regional pain syndrome: A prospective study of 13 patients at two centers. Neuromodulation 1999;2: 47-50
19. Rommel O, Malin JP, Zenz M, and Janig W. Quantitative sensory testing, neurophysiological and psychological examination in patients with complex regional pain syndrome and hemisensory deficits. Pain 2001;93: 279-293
20. van Rijn MA, Munts AG, Marinus J, Voormolen JH, de Boer KS, Teepe-Twiss IM, van Dasselaar NT, Delhaas EM, and van Hilten JJ. Intrathecal baclofen for dystonia of complex regional pain syndrome. Pain 2009;143: 41-47
21. Bruehl S, Harden RN, Galer BS, Saltz S, Bertram M, Backonja M, Gayles R, Rudin N, Bhugra MK, and Stanton-Hicks M. External validation of IASP diagnostic criteria for Complex Regional Pain Syndrome and proposed research diagnostic criteria.
International Association for the Study of Pain. Pain 1999;81: 147-154
22. Harden RN, Bruehl S, Galer BS, Saltz S, Bertram M, Backonja M, Gayles R, Rudin N, Bhugra MK, and Stanton-Hicks M. Complex regional pain syndrome: are the IASP diagnostic criteria valid and sufficiently comprehensive? Pain 1999;83: 211-219 23. Veldman PH, Reynen HM, Arntz IE, and Goris RJ. Signs and symptoms of reflex
sympathetic dystrophy: prospective study of 829 patients. Lancet 1993;342: 1012- 1016
24. Miller, R. G. Stimultaneous statistical inference. New York, NY: Springer; 1981 25. Newcombe RG. Improved confidence intervals for the difference between binomial
proportions based on paired data. Statistics in Medicine 1998;17: 2635-2650
26. Harden RN, Bruehl S, Stanton-Hicks M, and Wilson PR. Proposed new diagnostic criteria for complex regional pain syndrome. Pain Med 2007;8: 326-331
27. de Rooij AM, de Mos M, Sturkenboom MC, Marinus J, van den Maagdenberg AM, and van Hilten JJ. Familial occurrence of complex regional pain syndrome. Eur J Pain 2009;13: 171-177
28. Veldman PH and Goris RJ. Multiple reflex sympathetic dystrophy. Which patients are at risk for developing a recurrence of reflex sympathetic dystrophy in the same or another limb. Pain 1996;64: 463-466
29. Perez RS, Zuurmond WW, Bezemer PD, Kuik DJ, van Loenen AC, de Lange JJ, and Zuidhof AJ. The treatment of complex regional pain syndrome type I with free radical scavengers: a randomized controlled study. Pain 2003;102: 297-307
30. Quisel A, Gill JM, and Witherell P. Complex regional pain syndrome: which treatments show promise? J Fam Pract 2005;54: 599-603
Spontaneous onset of Complex Regional Pain Syndrome
39 31. de Mos M, Huygen FJ, van der Hoeven-Borgman M, Dieleman JP, Stricker BH, and
Sturkenboom MC. Outcome of the Complex Regional Pain Syndrome. Clin J Pain 2009;25: 590-597
32. Sandroni P, Benrud-Larson LM, McClelland RL, and Low PA. Complex regional pain syndrome type I: incidence and prevalence in Olmsted county, a population-based study. Pain 2003;103: 199-207
33. Perez RS, Collins S, Marinus J, Zuurmond WW, and de Lange JJ. Diagnostic criteria for CRPS I: differences between patient profiles using three different diagnostic sets.
Eur J Pain 2007;11: 895-902
34. LeMay LG, Vander AJ, and Kluger MJ. The effects of psychological stress on plasma interleukin-6 activity in rats. Physiol Behav 1990;47: 957-961
35. Garcia-Bueno B, Caso JR, and Leza JC. Stress as a neuroinflammatory condition in brain: damaging and protective mechanisms. Neurosci Biobehav Rev 2008;32: 1136- 1151
36. Huygen FJ, de Bruijn AG, De Bruin MT, Groeneweg JG, Klein J, and Zijistra FJ.
Evidence for local inflammation in complex regional pain syndrome type 1.
Mediators Inflamm 2002;11: 47-51
37. Birklein F and Schmelz M. Neuropeptides, neurogenic inflammation and complex regional pain syndrome (CRPS). Neurosci Lett 2008;437: 199-202
38. de Mos M, Huygen FJ, Dieleman JP, Koopman JS, Stricker BH, and Sturkenboom MC. Medical history and the onset of complex regional pain syndrome (CRPS). Pain 2008;139: 458-466
39. de Mos M, Huygen FJ, Dieleman JP, Koopman JS, Stricker BH, and Sturkenboom MC. Medical history and the onset of complex regional pain syndrome (CRPS). Pain 2008;139: 458-466
40. Merritt WH. The challenge to manage reflex sympathetic dystrophy/complex regional pain syndrome. Clin Plast Surg 2005;32: 575-604
